Compounds, their preparation and use

ABSTRACT

The present invention relates to compounds of the general formula (I)                    
     The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119 of Danishapplication PA 1999 00535 filed on Apr. 20, 1999, and U.S. applicationSer. No. 60/133,100 filed on May 7, 1999, the contents of which arefully incorporated herein by reference. This application is acontinuation of application Ser. No. 09/551,497, filed on Apr. 18, 2000now abandoned, the contents of which are fully incorporated byreference.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing them, methods for preparing the compounds andtheir use as medicaments. More specifically, compounds of the inventioncan be utilised in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR).

BACKGROUND OF THE INVENTION

Coronary artery disease (CAD) is the major cause of death in Type 2diabetic and metabolic syndrome patients (i.e. patients that fall withinthe ‘deadly quartet’ category of impaired glucose tolerance, insulinresistance, hypertriglyceridaemia and/or obesity).

The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

PPARα is involved in stimulating β-oxidation of fatty acids. In rodents,a PPARα-mediated change in the expression of genes involved in fattyacid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

A number of compounds have been reported to be useful in the treatmentof hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. No.5,306,726, PCT Publications nos. W091/19702, WO 95/03038, WO 96/04260,WO 94/13650, WO 94/01420, WO 97/36579,

WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313 and WO 99/16758).

SUMMARY OF THE INVENTION

Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia. The clinical activity of fibrates andthiazolidinediones indicates that research for compounds displayingcombined PPARα and PPARγ activation should lead to the discovery ofefficacious glucose and triglyceride lowering drugs that have greatpotential in the treatment of Type 2 diabetes and the metabolic syndrome(i.e. impaired glucose tolerance, insulin resistance,hypertriglyceridaemia and/or obesity).

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to compounds of the generalformula (I):

wherein ring A and ring B, fused to the ring containing X and T,independently of each other represents a 5-6 membered cyclic ring,optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro, cyano, formyl, or C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, C₁₋₁₂-alkoxy, aryloxy, arylalkyl, arylalkoxy,heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy,hydroxyC₁₋₁₂-alkyl, amino, acylamino, C₁₋₁₂-alkyl-amino, arylamino,arylalkylamino, amino-C₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl,aryloxycarbonyl, arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl,aryloxyC₁₋₁₂-alkyl, arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio,thioC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, bicycloalkyl, (C₃₋₆-cycloalkyl)C₁₋₆-alkyl,C₁₋₆dialkylamino, C₁₋₆alkylsulfonyl, C₁₋₆-monoalkylaminosulfonyl,C₁₋₆dialkylaminosulfonyl, arylthio, arylsulfonyl,C₁₋₆-monoalkylaminocarbonyl, C₁₋₆-dialkylaminocarbonyl, —COR⁶ or —SO₂R⁷,wherein R⁶ and R⁷ independently of each other are selected from hydroxy,halogen, perhalomethyl, C₁₋₆-alkoxy or amino optionally substituted withone or more C₁₋₆-alkyl or perhalomethyl; or aryl , wherein the aryloptionally can be substituted with one or more halogen, perhalomethyl,hydroxy, nitro or cyano; or heteroaryl, wherein the heteroaryloptionally can be substituted with halogen, amino hydroxy, C₁₋₆-alkyl orC₁₋₆-alkoxy; or heterocyclyl, wherein the heterocyclyl optionally can besubstituted with halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy;

X is a valence bond, —(CHR⁸)—, —(CHR⁸)—CH₂—, —CH═CH—, —O—(CHR⁸)—,—S—(CHR⁸)—, —(NR⁸)—CH₂—, —(CHR⁸)—CH═CH—, —(CHR⁸)—CH₂—CH₂—, —(C═O)—,—O—CH₂—O—, —(NR⁸)—S(O₂)—, —CH═(CR⁸)—, —(CO)—(CHR⁸)—, —CH₂—(SO)—, —(SO)—,—(SO₂)—, —CH₂—(SO₂)—, —CH₂—O—CH₂—, wherein R⁸ is hydrogen, halogen,hydroxy, nitro, cyano, formyl, C₁₋₁₂-alkyl, C₁₋₁₂-alkoxy, aryl, aryloxy,arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, C₁₋₁₂-alkyl-amino, arylamino, arylalkylamino,aminoC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl, aryloxycarbonyl,arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl, aryloxyC₁₋₁₂-alkyl,arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio, thioC₁₋₁₂-alkyl,C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, —COR or —SO₂R¹⁰, wherein R⁹ and R¹⁰independently of each other are selected from hydroxy, halogen,C₁₋₆l-alkoxy, amino optionally substituted with one or more C₁₋₆-alkyl,perhalomethyl or aryl;

T is N or CR¹⁴, wherein R¹⁴ is hydrogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl or arylalkyl;

Y is C, O, S, CO, SO, SO₂ or NR¹¹, wherein R¹¹ is hydrogen, C₁₋₆alkyl;

k is 1 or 2;

represents a single or a double bond;

Ar represents arylene, heteroarylene, or a divalent heterocyclic groupeach of which can optionally be substituted with one or morehalogen,C₁₋₆-alkyl, amino, hydroxy, C₁₋₆-alkoxy or aryl;

R¹ represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano;

R² represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano; or R² forms a bond together with R³;

R³ represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, acyl or arylalkyl;optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro or cyano; or R³ forms a bond together with R²;

R⁴ represents hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl orheteroarylalkyl groups; optionally substituted with one or more halogen,perhalomethyl, hydroxy, nitro or cyano;

R⁵ represents hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl orheteroarylalkyl groups; optionally substituted with one or more halogen,perhalomethyl, hydroxy, nitro or cyano;

Z represents oxygen or NR¹², wherein R¹² represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Z isNR¹², R⁴ and R¹² may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆-alkyl;

Q represents oxygen or NR¹³, wherein R¹³ represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Q isNR¹³, R⁵ and R¹³ may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆-alkyl;

n is an integer ranging from 0 to 3;

m is an integer ranging from 0 to 1;

p is an integer ranging from 0 to 1;

or a salt thereof with a pharmaceutically acceptable acid or base, orany optical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

In one embodiment, the present invention is concerned with compounds offormula I wherein ring A and ring B, fused to the ring containing X andT independently of each other represents a 5-6 membered cyclic ring,optionally substituted with halogen, C₁₋₆-alkyl or aryl, wherein thearyl can be substituted with one or more halogen or C₁₋₆-alkyl; orheterocyclyl, wherein the heterocyclyl can be substituted withC₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein ring A and ring B, fused to the ring containing Xand T independently of each other represents a 5-6 membered cyclic ring,optionally substituted with heterocyclyl, wherein the heterocyclyl canbe substituted with C₁₋₆alkyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein ring A and ring B, fused to the ring containing Xand T independently of each other represents aryl or pyridyl, optionallysubstituted with oxadiazolyl, wherein the oxadiazolyl can be substitutedwith C₁₋₄-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein X is a valence bond, —(CHR⁸)—, —(CHR⁸)—CH₂—,—O—(CHR⁸)— or —S—(CHR⁸)—, wherein R⁸ is hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula I wherein X is a valence bond, —(CHR⁸)—CH₂— or —S—(CHR⁸)—,wherein R⁸ is hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula I wherein T is N or CR¹⁴ wherein R¹⁴ is hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula I wherein Y is C, O or S.

In another embodiment, the present invention is concerned with compoundsof formula I wherein k is 2.

In another embodiment, the present invention is concerned with compoundsof formula I wherein represents a single bond.

In another embodiment, the present invention is concerned with compoundsof formula I wherein Ar represents arylene.

In another embodiment, the present invention is concerned with compoundsof formula I wherein R¹, R² and R³ represents hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula I wherein R⁴ and R⁵ represents hydrogen or methyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein Z and Q represents O.

In another embodiment, the present invention is concerned with compoundsof formula I wherein n is 1.

In another embodiment, the present invention is concerned with compoundsof formula I wherein m is 1.

In another embodiment, the present invention is concerned with compoundsof formula I wherein p is 0.

In specific embodiments, compounds of the invention are:

2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid dimethyl ester,

2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid,

2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonicacid dimethyl ester,

2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-β-carbolin-9-yl]-ethoxy}-benzyl)-malonicacid ester dimethyl; or a salt thereof with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.

In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

The term “C_(1-n′)-alkyl” wherein n′ can be from 2 through 12, as usedherein, represents a branched or straight or cyclic alkyl group havingfrom one to the specified number of carbon atoms. Examples of suchgroups include, but are not limited to methyl, ethyl, n-propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andthe like and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl and the like.

The terms “C_(2-n′)-alkenyl” wherein n′ can be from 3 through 15, asused herein, represents an olefinically unsaturated branched or straightgroup having from 2 to the specified number of carbon atoms and at leastone double bond. Examples of such groups include, but are not limitedto, vinyl, 1-propenyl, 2-propenyl, allyl, iso-proppenyl, 1,3-butadienyl,1-butenyl, hexenyl, pentenyl and the like.

The terms “C_(2-n′)-alkynyl” wherein n′ can be from 3 through 15, asused herein, represent an unsaturated branched or straight group havingfrom 2 to the specified number of carbon atoms and at least one triplebond. Examples of such groups include, but are not limited to,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl andthe like.

The terms “C_(4-n′)-alkenynyl” wherein n′ can be from 5 through 15, asused herein, represent an unsaturated branched or straight hydrocarbongroup having from 4 to the specified number of carbon atoms and both atleast one double bond and at least one triple bond. Examples of suchgroups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne,1,3-hexadiene-5-yne and the like.

The term “C₁₋₁₂-alkoxy” as used herein, alone or in combination isintended to include those C₁₋₁₂-alkyl groups of the designated length ineither a linear or branched or cyclic configuration linked through anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy and the like. Examples of branched alkoxy are isoprpoxy,sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like. Examples ofcyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and the like.

The term “C₁₋₁₂-alkylthio” as used herein, alone or in combination,refers to a straight or branched or cyclic monovalent substituentcomprising a C₁₋₁₂-alkyl group linked through a divalent sulfur atomhaving its free valence bond from the sulfur atom and having 1 to 12carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio,pentylthio and the like. Examples of cyclic alkylthio arecyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and thelike.

The term “C₁₋₁₂-alkylamino” as used herein, alone or in combination,refers to a straight or branched or cyclic monovalent substituentcomprising a C₁₋₁₂-alkyl group linked through amino having a freevalence bond from the nitrogen atom e.g. methylamino, ethylamino,propylamino, butylamino, pentylamino and the like. Examples of cyclicalkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and the like.

The term “hydroxyC₁₋₁₂-alkyl” as used herein, alone or in combination,refers to a C₁₋₁₂-alkyl as defined herein whereto is attached a hydroxygroup, e.g. hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.

The term “arylamino” as used herein, alone or in combination, refers toan aryl as defined herein linked through amino having a free valencebond from the nitrogen atom e.g. phenylamino, naphthylamino and thelike.

The term “arylalkylamino” as used herein, alone or in combination,refers to an arylalkyl as defined herein linked through amino having afree valence bond from the nitrogen atom e.g. benzylamino,phenethylamino, 3-phenylpropylamino, 1-naphtylmethylamino,2-(1-naphtyl)ethylamino and the like.

The term “aminoC₁₋₁₂-alkyl” as used herein, alone or in combination,refers to a C₁₋₁₂-alkyl as defined herein whereto is attached an aminogroup, e.g. aminoethyl, 1-aminopropyl, 2-aminopropyl and the like.

The term “aryloxycarbonyl” as used herein, alone or in combination,refers to an aryloxy as defined herein linked through a carbonyl havinga free valence bond from the carbon atom, e.g. phenoxycarbonyl,1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl and the like.

The term “arylalkoxycarbonyl” as used herein, alone or in combination,refers to an arylalkoxy as defined herein linked through a carbonylhaving a free valence bond from the carbon atom, e.g. benzyloxycarbonyl,phenethoxycarbonyl, 3-phenylpropoxycarbonyl, 1-naphthylmethoxycarbonyl,2-(1-naphtyl)ethoxycarbonyl and the like.

The term “C₁₋₁₂-alkoxyC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached a C₁₋₁₂-alkoxy as defined herein, e.g. methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

The term “aryloxyC₁₋₁₂-alkyl” as used herein, alone or in combination,refers to a C₁₋₁₂-alkyl as defined herein whereto is attached an aryloxyas defined herein, e.g. phenoxymethyl, phenoxydodecyl,1-naphthyloxyethyl, 2-naphthyloxypropyl and the like.

The term “arylalkoxyC₁₋₂-alkyl” as used herein, alone or in combination,refers to a C₁₋₁₂-alkyl as defined herein whereto is attached anarylalkoxy as defined herein, e.g. benzyloxymethyl, phenethoxydodecyl,3-phenylpropoxyethyl, 1-naphthylmethoxypropyl, 2-(1-naphtyl)ethoxymethyland the like.

The term “thioC₁₋₁₂-alkyl” as used herein, alone or in combination,refers to a C₁₋₁₂-alkyl as defined herein whereto is attached a group offormula —SR′″ wherein R′″ is hydrogen, C₁₋₆alkyl or aryl, e.g.thiomethyl, methylthiomethyl, phenylthioethyl and the like.

The term “C₁₋₁₂-alkoxycarbonylamino” as used herein, alone or incombination, refers to a C₁₋₁₂-alkoxycarbonyl as defined herein linkedthrough amino having a free valence bond from the nitrogen atom e.g.methoxycarbonylamino, carbethoxyamino, propoxycarbonylamino,isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylaminoand the like.

The term “aryloxycarbonylamino” as used herein, alone or in combination,refers to an aryloxycarbonyl as defined herein linked through aminohaving a free valence bond from the nitrogen atom e.g.phenoxycarbonylamino, 1-naphthyloxycarbonylamino or2-naphthyloxycarbonylamino and the like.

The term “arylalkoxycarbonylamino” as used herein, alone or incombination, refers to an arylalkoxycarbonyl as defined herein linkedthrough amino having a free valence bond from the nitrogen atom e.g.benzyloxycarbonylamino, phenethoxycarbonylamino,3-phenylpropoxycarbonylamino, 1-naphthylmethoxycarbonylamino,2-(1-naphtyl)ethoxycarbonylamino and the like.

The term “aryl” is intended to include aromatic rings, such ascarboxylic aromatic rings selected from the group consisting of phenyl,naphthyl, (1-naphtyl or 2-naphtyl) and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy and the like.

The term “arylene” is intended to include divalent aromatic rings, suchas carboxylic aromatic rings selected from the group consisting ofphenylene, naphthylene and the like optionally substituted with halogen,amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl.

The term “C₁₋₆-dialkylamino” as used herein refers to an amino groupwherein the two hydrogen atoms independently are substituted with astraight or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino,diethylamino, dipropylamino, N-(n-butyl)-N-methylamino,di(n-pentyl)amino and the like.

The term “acyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkyl group linked through a carbonyl group; such ase.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and thelike.

The term “acyloxy” as used herein refers to acyl as defined hereinlinked to an oxygen atom having its free valence bond from the oxygenatom e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pivaloyloxy, valeryloxy and the like.

The term “C₁₋₁₂-alkoxycarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₁₂-alkoxy group linked through a carbonylgroup; such as e.g. methoxycarbonyl, carbethoxy, propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and thelike.

The term “bicycloalkyl” as used herein refers to a monovalentsubstituent comprising a bicyclic structure made of 6-12 carbon atomssuch as e.g. 2-norbornyl, 7-norbornyl, 2-bicyclo[2.2.2]octyl and9-bicyclo[3.3.1]nonanyl and the like.

The term “heteroaryl” as used herein, alone or in combination, refers toa monovalent substituent comprising a 5-6 membered monocyclic aromaticsystem or a 9-10 membered bicyclic aromatic system containing one ormore heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like.

The term “heteroarylene” as used herein, alone or in combination, refersto a divalent group comprising a 5-6 membered monocyclic aromatic systemor a 9-10 membered bicyclic aromatic system containing one or moreheteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like.

The term “heteroaryloxy” as used herein, alone or in combination, refersto a heteroaryl as defined herein linked to an oxygen atom having itsfree valence bond from the oxygen atom e.g. pyrrole, imidazole,pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine,isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline,isoquinoline, quinazoline, quinoxaline, indole, benzimidazole,benzofuran, pteridine and purine linked to oxygen, and the like.

The term “arylalkyl” as used herein refers to a straight or branchedsaturated carbon chain containing from 1 to 6 carbons substituted withan aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl,1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.

The term “aryloxy” as used herein refers to phenoxy, 1-naphthyloxy,2-naphthyloxy and the like.

The term “arylalkoxy” as used herein refers to a C₁₋₆-alkoxy groupsubstituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy andthe like.

The term “heteroarylalkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with a heteroaryl group; such as (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.

The term “heteroarylalkoxy” as used herein refers to a heteroarylalkylas defined herein linked to an oxygen atom having its free valence bondfrom the oxygen atom, e.g. (2-furyl)methyl, (3-furyl)methyl,(2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl,1-methyl-1-(2-pyrimidyl)ethyl linked to oxygen, and the like.

The term “C₁₋₆alkylsulfonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-alkyl group linked through a sulfonylgroup such as e.g. methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl, n-hexylsulfonyl,4-methylpentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl,2,2-dimethylpropylsulfonyl and the like.

The term “C₁₋₆-monoalkylaminosulfonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆monoalkylamino group linkedthrough a sulfonyl group such as e.g. methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,n-butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl,tert-butylaminosulfonyl, n-pentylaminosulfonyl,2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl,n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl,neopentylaminosulfonyl, n-hexylaminosulfonyl,2,2-dimethylpropylaminosulfonyl and the like.

The term “C₁₋₆-dialkylaminosulfonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-dialkylamino group linkedthrough a sulfonyl group such as dimethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl,dipropylaminosulfonyl, N-(n-butyl)-N-methylaminosulfonyl,di(n-pentyl)aminosulfonyl and the like.

The term “acylamino” as used herein refers to an amino group wherein oneof the hydrogen atoms is substituted with an acyl group, such as e.g.acetamido, propionamido, isopropylcarbonylamino and the like.

The term “(C₃₋₆-cycloalkyl)C₁₋₆-alkyl” as used herein, alone or incombination, refers to a straight or branched, saturated hydrocarbonchain having 1 to 6 carbon atoms and being monosubstituted with aC₃₋₆-cycloalkyl group, the cycloalkyl group optionally being mono- orpolysubstituted with C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy; suchas e.g. cyclopropylmethyl, (1-methylcyclopropyl)methyl,1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

The term “arylthio” as used herein, alone or in combination, refers toan aryl group linked through a divalent sulfur atom having its freevalence bond from the sulfur atom, the aryl group optionally being mono-or polysubstituted with C₁₋₆alkyl, halogen, hydroxy or C₁₋₆-alkoxy; e.g.phenylthio, (4-methylphenyl)-thio, (2-chlorophenyl)thio and the like.

The term “arylsulfonyl” as used herein refers to an aryl group linkedthrough a sulfonyl group, the aryl group optionally being mono- orpolysubstituted with C₁₋₆alkyl, halogen, hydroxy or C₁₋₆alkoxy; such ase.g. phenylsulfonyl, tosyl and the like.

The term “C₁₋₆-monoalkylaminocarbonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-monoalkylamino group linkedthrough a carbonyl group such as e.g. methylaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl,n-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl,tert-butylaminocarbonyl, n-pentylaminocarbonyl,2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl,n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl,neopentylaminocarbonyl, n-hexylaminocarbonyl,2-2-dimethylpropylaminocarbonyl and the like.

The term “C₁₋₆-dialkylaminocarbonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆dialkylamino group linkedthrough a carbonyl group such as dimethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl,dipropylaminocarbonyl, N-(n-butyl)-N-methylaminocarbonyl,di(n-pentyl)aminocarbonyl and the like.

As used herein, the phrase “heterocyclyl” means a monovalent saturatedor unsaturated non aromatic group being monocyclic and containing one ormore, such as from one to four carbon atom(s), and from one to four N, Oor S atom(s) or a combination thereof. The phrase “heterocyclyl”includes, but is not limited to, 5-membered heterocycles having onehetero atom (e.g. pyrrolidine, pyrroline and the like); 5-memberedheterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g.pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imidazoline,4-oxazolone and the like); 5-membered heterocycles having threeheteroatoms (e.g. tetrahydrofurazan and the like); 5-memberedheterocycles having four heteroatoms; 6-membered heterocycles with oneheteroatom (e.g. piperidine and the like); 6-membered heterocycles withtwo heteroatoms (e.g. piperazine, morpholine and the like); 6-memberedheterocycles with three heteroatoms; and 6-membered heterocycles withfour heteroatoms, and the like.

As used herein, the phrase “a divalent heterocyclic group” means adivalent saturated or unsaturated system being monocyclic and containingone or more, such as from one to four carbon atom(s), and one to four N,O or S atom(s) or a combination thereof. The phrase a divalentheterocyclic group includes, but is not limited to, 5-memberedheterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and thelike); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,imidazolidine, imidazoline, 4-oxazolone and the like); 5-memberedheterocycles having three heteroatoms (e.g. tetrahydrofurazan and thelike); 5-membered heterocycles having four heteroatoms; 6-memberedheterocycles with one heteroatom (e.g. piperidine and the like);6-membered heterocycles with two heteroatoms (e.g. piperazine,morpholine and the like); 6-membered heterocycles with threeheteroatoms; and 6-membered heterocycles with four heteroatoms, and thelike.

As used herein, the phrase “a 5-6 membered cyclic ring” means anunsaturated or saturated or aromatic system containing one or morecarbon atoms and optionally from one to four N, O or S atom(s) or acombination thereof. The phrase “a 5-6 membered cyclic ring” includes,but is not limited to, e.g. cyclopentyl, cyclohexyl, phenyl,cyclohexenyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, 1,3-dioxolanyl, 1,4-dioxolanyl and the like,5-membered heterocycles having one hetero atom (e.g. thiophenes,pyrroles, furans and the like); 5-membered heterocycles having twoheteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles,imidazoles, thiazoles, purines and the like); 5-membered heterocycleshaving three heteroatoms (e.g. triazoles, thiadiazoles and the like);5-membered heterocycles having four heteroatoms; 6-membered heterocycleswith one heteroatom (e.g. pyridine, quinoline, isoquinoline,phenanthridine, cyclohepta[b]pyridine and the like); 6-memberedheterocycles with two heteroatoms (e.g. pyridazines, cinnolines,phthalazines, pyrazines, pyrimidines, quinazolines, morpholines and thelike); 6-membered heterocycles with three heteroatoms (e.g.1,3,5-triazine and the like); and 6-membered heterocycles with fourheteroatoms and the like.

Certain of the above defined terms may occur more than once in the aboveformula (I), and upon such occurrence each term shall be definedindependently of the other.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable base addition salts,pharmaceutically acceptable metal salts, ammonium and alkylated ammoniumsalts. Acid addition salts include salts of inorganic acids as well asorganic acids. Representative examples of suitable inorganic acidsinclude hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic,malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium salts and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula I with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents lilkeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts whereever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and thelike in solvents like ethyl acetate, ether, alcohols, acetone, THF,dioxane etc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula I may be converted to a1:1 mixture of diastereomeric amides by treating with chiral amines,amino acids, amino alcohols derived from amino acids; conventionalreaction conditions may be employed to convert acid into an amide; thedia-stereomers may be separated either by fractional crystallization orchromatography and the stereoisomers of compound of formula I may beprepared by hydrolysing the pure diastereomeric amide. Variouspolymorphs of compound of general formula I forming part of thisinvention may be prepared by crystallization of compound of formula Iunder different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

Furthermore, the present compounds of formula I can be utilised in thetreatment and/or prevention of conditions mediated by nuclear receptors,in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

In a further aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes, preferably TypeII diabetes.

In a still further aspect, the present invention relates to the use ofone or more compounds of the general formula I or pharmaceuticallyacceptable salts thereof for the preparation of a medicament for thetreatment and/or prevention of Type I or Type II diabetes, preferablyType II diabetes.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of IGT.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from IGT to Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

In still another aspect, the present compounds may also be useful forimproving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

The invention also relates to pharmaceutical compositions comprising, asan active ingredient, at least one compound of the formula I or anyoptical or geometric isomer or tautomeric form thereof includingmixtures of these or a pharmaceutically acceptable salt thereof togetherwith one or more pharmaceutically acceptable carriers or diluents.

Furthermore, the invention relates to the use of compounds of thegeneral formula I or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

A compound of formula I can be prepared as described below:

a) Reacting a compound of formula II, wherein A, B, T, X, Y, and p areas defined previously, except that T is not N,

 through a Wiltig process with (PH₃P)₃P(CH₂)_(n+1)OH.Br in the presenceof a suitable base as butyllithium, to give compounds of formula III.

 wherein A, B, X, Y, T, p and n are defined as previously, except that Tis not N. Compounds of formula III may then be reacted under Mitsunobuconditions with compounds of formula IV

 wherein m, R¹, R², R³ are defined as previously and wherein R⁴ and R⁵are defined as previously except H, to give compounds of formula 1,wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³ are defined aspreviously, except that T is not N, and wherein R⁴ and R⁵ are defined aspreviously except H, and wherein m and k is 1 and within the termT══(Y)_(p), ══ is defined as a single bond and within the termT(CH_(k)), is defined as a double bond.

b) Alternatively a compound of formula V

 wherein A, B, X, Y, T, p, n, k, and the terms T══(Y)_(p) andT══(CH_(k)) are defined as previously and wherein LG is a suitableleaving group, may be reacted, possible under transition metalcatalysis, with a nucleophilic compound of formula VI

 wherein Ar, R¹, R², R³ are defined as previously and wherein R⁴ and R⁵are defined as previously except H and wherein “Met” is a metal such aszinc or copper, carrying suitable ligands preferentially fromtrifluoro-methanesulfonate or halide to give compounds of formula I,wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³, and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously and wherein R⁴ andR⁵ are defined as previously except H, and wherein m is 0.

c) Alternatively compounds of formula V wherein A, B, X, Y, T, p, n, andthe terms T══(Y)_(p) and T══(CH_(k)) are defined as previously andwherein LG is a suitable leaving group (for example halogen, sulfonates,phosphor, hydroxy under Mitsunobu conditions) are reacted with acompound of VII

 wherein Ar, Z, Q, R¹, R², R³ are defined as previously and wherein R⁴and R⁵ are defined as previously except H, to give compounds of formula1, wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³, and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously and wherein R⁴ andR⁵ are defined as previously except H, and wherein m is 1.

d) Alternatively a compound of formula VIII

 wherein A, B, X, Y and p are defined as previously, may be alkylatedwith a suitable electrophilic reagent such as ethylene oxide, ethylbromoacetate followed by reduction of the ester to an alcohol,2-bromoethanol or 2-bromoethanol to give a compound of formula X

 wherein A, B, X, Y, p and n are defined as previously. The hydroxygroup can if needed be converted to a suitable leaving group and reactedwith a compound of formula VII, wherein Ar, Z, Q, R¹, R², R³ are definedas previously and wherein R⁴ and R⁵ are defined as previously except H,to give compounds of formula 1, wherein A, B, X, Y, Ar, Z, Q, p, n, R¹,R² and R³ are defined as previously and within the terms T══(Y)_(p) andT══(CH_(k)), ══ is defined as a singlebond and wherein R⁴ and R⁵ aredefined as previously except H, and wherein m is 1 and k is 0 andwherein T is N.

e) Alternatively reacting compounds of formula X wherein A, B, X, Y, pand n are defined as previously, with a compound of formula XI

 wherein Ar is defined as previously, followed by reaction with asuitable Wittig reagent to give a compound of formula XII

 wherein A, B, X, Y, Ar, Z, Q, p, n, R¹, R², R³, and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously and wherein R⁴ andR⁵ are defined as previously except H. Addition to the double bond ofsuitable reagents give compounds of formula I, wherein A, B, X, Y, Ar,Z, Q, p, n, R¹, R² and R³ are defined as previously and within the termsT══(Y)_(p) and T══(CH_(k)), ══ is defined as a single bond and whereinR⁴ and R⁵ are defined as previously except H, and wherein m is 1 and kis 0 and wherein T is N.

f) Alternatively compounds of formula I wherein A, B, X, Y, T, Ar, p, n,k, R¹, R², R³, and the terms T══(Y)_(p) and T══(CH_(k)) are defined aspreviously and wherein Z and Q is O and wherein R⁴ and R⁵ are defined aspreviously except H can either be hydrolysed to the corresponding acidor be reacted further to give a compound of formula I wherein A, B, X,Y, T, Ar, Z. Q, p, n, R¹, R², R³, R⁴, R⁵ and the terms T══(Y)_(p) andT══(CH_(k)) are defined as previously.

Pharmacological Methods

In vitro PPAR alpha and PPAR gamma activation activity.

Principle: The PPAR gene transcription activation assays were based ontransient transfection into human HEK293 cells of two plasmids encodinga chimeric test protein and a reporter protein respectively. Thechimeric test protein was a fusion of the DNA binding domain (DBD) fromthe yeast GAL4 transcription factor to the ligand binding domain (LBD)of the human PPAR proteins. The PPAR LBD harbored in addition to theligand binding pocket also the native activation domain (activatingfunction 2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will force the fusionprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand, luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

Methods: Cell culture and transfection: HEK293 cells were grown inDMEM+10% FCS, 1% PS. Cells were seeded in 96-well plates the day beforetransfection to give a confluency of 80% at transfection. 0,8 μg DNA perwell was transfected using FuGene transfection reagent according to themanufacturers instructions (Boehringer-Mannheim). Cells were allowed toexpress protein for 48 h followed by addition of compound.

Plasmids: Human PPAR α and β was obtained by PCR amplification usingcDNA templates from liver, intestine and adipose tissue respectively.Amplified cDNAs were cloned into pCR^(2.1) and sequenced. The LBD fromeach isoform PPAR was generated by PCR (PPARα: aa 167- C-term; PPARγ: aa165- C-term) and fused to GAL4-DBD by subcdoning fragments in frame intothe vector pM1 generating the plasmids pM1αLBD and pM1γLBD. Ensuingfusions were verified by sequencing. The reporter was constructed byinserting an oligonucleotide encoding five repeats of the Gal4recognition sequence into the pGL2 vector (Promega).

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Cells were treated with compound (1:1000 in 200μl growth medium including delipidated serum) for 24 h followed byluciferase assay.

Luciferase assay: Medium including test compound was aspirated and 100μl PBS incl. 1 mM Mg++ and Ca++ was added to each well. The luciferaseassay was performed using the LucLite kit according to the manufacturersinstructions (Packard Instruments). Light emission was quantified bycounting SPC mode on a Packard Instruments top-counter.

Pharmaceutical Compositions

In another aspect, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent. The present compoundsmay also be administered in combination with one or more furtherpharmacologically active substances eg. selected from antiobesityagents, antidiabetics, antihypertensive agents, agents for the treatmentand/or prevention of complications resulting from or associated withdiabetes and agents for the treatment and/or prevention of complicationsand disorders resulting from or associated with obesity.

Thus, in a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

In one embodiment of the invention the antiobesity agent is leptin. Inanother embodiment the antiobesity agent is dexamphetamine oramphetamine. In another embodiment the antiobesity agent is fenfluramineor dexfenfluramine. In still another embodiment the antiobesity agent issibutramine. In a further embodiment the antiobesity agent is orlistat.In another embodiment the antiobesity agent is mazindol or phentermine.Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1)derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S,which is incorporated herein by reference as well as orally activehypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

In one embodiment of the invention the present compounds areadministered in combination with insulin.

In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

In yet another embodiment the present compounds are administered incombination with a meglitinide eg. repaglinide.

In a further embodiment the present compounds are administered incombination with an a-glucosidase inhibitor eg. miglitol or acarbose.

In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

Furthermore, the present compounds may be administered in combinationwith nateglinide.

In still another embodiment the present compounds are administered incombination with an antihyperlipidemic agent or antilipidemic agent eg.cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol or dextrothyroxine.

In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and mefformin, a sulphonylurea andacarbose, repaglinide and mefformin, insulin and a sulphonylurea,insulin and mefformin, insulin, insulin and lovastatin, etc.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and α-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995. It should be understood that any suitablecombination of the compounds according to the invention with one or moreof the above-mentioned compounds and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present invention.

Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: The Science and Practise of Pharmacy, 19^(th) Ed., 1995.The compositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet which may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt thereof)   5 mgColloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.(Avicel)  70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesiumstearate Ad. Coating: HPMC approx.   9 mg *Mywacett 9-40 T approx. 0.9mg *Acylated monoglyceride used as plasticizer for film coating.

The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

Such mammals include also animals, both domestic animals, e.g. householdpets, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 100 mg, preferably from about 0.1 to about 100 mg, per day maybe used. A most preferable dosage is about 0.1 mg to about 70 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a dosage of from about 2 to about 70 mg per day and whenthe condition is under control to reduce the dosage as low as from about0.1 to about 10 mg per day. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

Generally, the compounds of the present invention are dispensed in unitdosage form comprising from about 0.1 to about 100 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

Usually, dosage forms suitable for oral, nasal, pulmonary or transdermaladministration comprise from about 0.001 mg to about 100 mg, preferablyfrom about 0.01 mg to about 50 mg of the compounds of formula I admixedwith a pharmaceutically acceptable carrier or diluent.

Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry(MS). NMR shifts (δ) are given in parts per million (ppm) and onlyselected peaks are given. mp is melting point and is given in ° C.Column chromatography was carried out using the technique described byW.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel60 (Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se.

Abbrevations: TLC: thin layer chromatography DMSO: dimethylsulfoxideCDCl₃: deutorated chloroform DMF: N,N-dimethylformamide min: minutes h:hours

Example 1

2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic Acid Dimethyl Ester

a) A solution of benzyloxybenzaldehyde (10.6 g, 50.0 mmol) and dimethylmalonate (6.6 g, 50.0 mmol) in benzene (100 mL) containing a catalyticquantity of pipiridinium acetate was refluxed in a Dean-Stark trap for16 h. After cooling to room temperature, the solution was concentrated.The residue was crystallised from ethyl acetate/heptane to give 14.5 g(90%) of 2-(4-benzyloxy-benzylidene)-malonic acid dimethyl ester: mp134-135° C. ¹H NMR (300 MHz, CDCl₃): δ 3.82 (s, 3H), 3.86 (s, 3H), 5.08(s, 2H), 6.95 (d, 2H), 7.30-7.45 (m, 7H), 7.70 (s, 1H).

b) A solution of 2-(4-benzyloxy-benzylidene)-malonic acid dimethyl ester(14,5 g, 44.5 mmol) in methanol (300 mL) was hydrogenated at 3 atm. inthe presence of 5% palladium on charcoal (1.1 g). The solution wasfiltered, and the filtrate evaporated under a vacuum to give 9.2 g (77%)of 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester: ¹H NMR (300 MHz,CDCl₃): δ 3.15 (d, 2H), 3.65 (t, 1H), 3.70 (s, 6H), 6.70 (d, 2H), 7.05(d, 2H).

c) To a −30° C. cooled solution of 9H-β-carboline (1.0 g, 5.95 mmol) indry THF (30 mL) was added butyllithium (4.12 mL, 6.55 mmol) over a 15min period. After 30 min at −30° C., the reaction mixture was cooled to−50° C. Ethylene oxide (1.6 mL in a cooled measuring cylinder) was thenbubbled into the reaction mixture, in a stream of nitrogen. Thetemperature was slowly raised to −5° C. over a 2 h period, and stirringwas continued for 84 h. The mixture was acidified with 1 N HCl (50 mL)and extracted with diclormethane (2×100 mL). The combined extracts weredried (MgSO₄), and concentrated in vacuo. The product waschromatographed eluted with dichloromethan/methanol (20:1) to give 660mg (53%) of 2-β-carbolin-9-yl-ethanol. ¹H NMR (300 MHz, CDCl₃): δ 3.62(s, 1H), 4.10 (t, 2H), 4.50 (t, 2H), 7.30 (t, 1H), 7.50-7.65 (m, 2H),7.80 (d, 1H), 8.10 (d, 1H), 8.22 (d, 1H), 8.78 (s, 1H).

d) Under a nitrogen atmosphere, 2-β-carbolin-9-yl-ethanol (212 mg, 1.0mmol), tributylphosphine (303 mg, 1.5 mmol) and2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (238 mg, 1.0 mmol) weresuccessively dissolved in dry benzene (40 mL). Solid azodicarboxylicdipiperidide (ADDP) (378 mg, 1.5 mmol) was added under stirring at 0° C.to the solution. After 10 min, the reaction mixture was brought to roomtemperature and the stirring was continued for 16 h. Heptane (10 mL) wasadded to the reaction mixture and dihydro-ADDP separated out wasfiltered off. After evaporation of the solvent the product waschromatographed eluting with dichloromethane graduated with ethylacetate to give 355 mg (82%) of the title compound; ¹H NMR (300 MHz,CDCl₃): δ 3.10 (d, 2H), 3.55 (t, 1H), 3.65 (s, 6H), 4.35 (t, 2H), 4.75(t, 2H), 6.70 (d, 2H), 7.05 (d, 2H), 7.30 (t, 1H), 7.3-7.63 (m, 2H),7.97 (d, 1H), 8.13 (d, 1H), 8.48 (d, 1H), 9.02 (s,1H).

Example 2

2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic Acid, Hydrochloride

A 1 N aqueous solution of sodium hydroxide (3 mL) was added to asolution of 2-[4-(2-β-carbolin-9-yl-ethoxy)-benzyl]-malonic aciddimethyl ester (185 mg, 0.34mmol) in a mixture of methanol (3 mL) andtetrahydrofuran (3 mL).The mixture was stirred for 64 h at roomtemperature. After evaporation of organic solvent, water was added, andthe mixture was acidified with 1 N hydrochloric acid. The product wasextracted with a mixture of dichloromethane/isopropanol. The combinedorganic extract was dried (MgSO₄) and concentrated to give the titlecompound (25 mg, 16%); ¹H NMR (300 MHz, CDCl₃): δ 2.99 (d, 2H), 3.47 (t,1H), 4.44(t, 2H), 5.05 (t, 2H), 6.60 (d, 2H), 3.00 (d, 2H), 7.55 (t,1H), 7.85-8.00 (m, 2H), 8.59 (t, 2H), 8.70 (d, 1 H), 9.35 (s, 1 H).

Example 3

2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonicAcid Dimethyl Ester

The title compound was prepared from iminodibenzyl (3.0 g, 15.3 mmol),by a sequence analogous to that described in example 1.

¹H NMR (300 MHz, CDCl₃): δ 3.13 (d, 2H), 3.15 (s, 4H), 3.60 (s, 1H),3.68 (s, 6H), 4.03 (t, 2H), 4.17 (t, 2H), 6.70 (d, 2H), 6.88-6.98 (m,2H), 7.00-7.15 (m, 8H).

Example 4

2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-β-carbolin-9-yl]-ethoxy}-benzyl)-malonicAcid Ester Dimethyl

a) Under a nitrogen atmosphere, 2-benzyloxyethanol (30.4 g, 0.2 mol),tributylphosphine (50.4 g, 0.2 mol) and 2-(4-hydroxy-benzyl)-malonicacid dimethyl ester (example 1b) (42.9 g, 0.18 mol) were successivelydissolved in dry benzene (1.5 L). Solid azodicarboxylic dipiperidide(ADDP) (40.4 g, 0.2 mol) was added under stirring at 0° C. to thesolution. After 10 min, the reaction mixture was brought to roomtemperature and the stirring was continued for 16 h. Heptane (0.5 L) wasadded and the precipitate was filtered off. After evaporation of thesolvent the product was chromatographed eluting with heptane graduatedwith ethyl acetate to give 64.0 g (96%) of2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethyl ester.

¹H NMR (300 MHz, CDCl₃): δ 3.15 (d, 2H), 3.63 (t, 1H), 3.70 (s, 6H),3.82 (t, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 6.84 (d, 2H), 7.10 (d, 2H),7.30-7.40 (m, 5H).

b) A solution of 2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethylester (64.0 g, 172 mmol) in ethyl acetate (700 mL) was hydrogenated at 3atm. in the presence of 10% palladium on charcoal (3.0 g). The solutionwas filtered, and the filtrate evaporated under vacuo to give2-[4-(2-hydroxy-ethoxy)-benzyl]-malonic acid dimethyl ester. ¹H NMR (300MHz, CDCl₃): δ2.06 (bs, 1H), 3.18 (d, 2H), 3.63 (t, 1H), 3.70 (s, 6H),3.94 (t, 2H), 4.05 (t, 3H), 6.83 (d, 2H), 7.12 (d, 2H).

c) Under a nitrogen atmosphere, 2-[4-(2-hydroxy-ethoxy)-benzyl]-malonicacid dimethyl ester (420 mg, 1.5 mmol), tributylphosphine (303 mg, 1.5mmol) and 3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-9H-β-carboline (276 mg,1.0 mmol) were successively dissolved in dry benzene (15 mL). Solidazodicarboxylic dipiperidide (ADDP) (380 mg, 1.5 mmol) was added understirring at 0° C. to the solution. After 10 min, the reaction mixturewas brought to room temperature and the stirring was continued for 16 h.The reaction mixture was cooled on ice again and added another portionof tributylphosphine (303 mg, 1.5 mmol) and ADDP) (380 mg, 1.5 mmol).After 10 min, the reaction mixture was brought to room temperature andthe stirring was continued for another 16 h. The reaction mixture wasconcentrated in vacuo and the residue chromatographed to give 217 mg(40%) of the title compound.

¹H NMR (300 MHz, CDCl₃): δ1.48 (d, 6H), 3.10 (d, 2H), 3.20-3.32 (m, 1H),3.57 (t, 1H), 3.65 (s, 6H), 4.40 (t, 2H), 4.85 (t, 2H), 6.68 (d, 2H),7.03 (d, 2H), 7.42 (t, 1H), 7.60-7.72 (m, 2), 8.24 (d, 1H), 8.90 (s,1H), 9.20 (s, 1H).

What is claimed is:
 1. A compound of formula (I)

wherein ring A and ring B, fused to the ring containing X and T,independently of each other represents aryl or pyridyl, optionallysubstituted with oxadiazolyl, wherein the oxadiazolyl can be substitutedwith C₁₋₄-alkyl; X is a valence bond; T is N; Y is C; k is 1 or 2; ═represents a single or a double bond; Ar is arylene, heteroarylene, or adivalent heterocyclic group each of which can optionally be substitutedwith one or more halogen,C₁₋₆-alkyl, amino, hydroxy, C₁₋₆-alkoxy oraryl; R¹ is hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano; R² is hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano; or R² forms a bond together with R³; R³ is hydrogen, hydroxy,halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, acyl or arylalkyl; optionally substituted with one ormore halogen, perhalomethyl, hydroxy, nitro or cyano; or R³ forms a bondtogether with R²; R⁴ is hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, arylalkyl heterocyclyl, heteroarylor heteroarylalkyl groups; optionally substituted with one or morehalogen, perhalomethyl, hydroxy, nitro or cyano; R⁵ is hydrogen,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl,arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups;optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro or cyano; Z is oxygen or NR¹², wherein R¹² represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Z isNR¹², R⁴ and R¹² may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆alkyl; Q is oxygen or NR¹³,wherein R¹³ represents hydrogen C₁ ₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl orarylalkyl groups or when Q is NR¹³, R⁵ and R¹³ may form a 5 or 6membered nitrogen containing ring, optionally substituted with one ormore C₁₋₆-alkyl; n is an integer ranging from 0 to 3; m is an integerranging from 0 to 1; p is an integer ranging from 0 to 1; or a saltthereof with a pharmaceutically acceptable acid or base, or any opticalisomer or mixture of optical isomers, including a racemic mixture, orany tautomeric forms.
 2. The compound of claim 1, wherein k is
 2. 3. Thecompound of claim 1, wherein ═ represents a single bond.
 4. The compoundof claim 1, wherein Ar represents arylene.
 5. The compound of claim 1,wherein R¹, R² and R³ represents hydrogen.
 6. The compound of claim 1,wherein R⁴ and R⁵ represents hydrogen or methyl.
 7. The compound ofclaim 1, wherein Z and Q represents O.
 8. The compound of claim 1,wherein n is
 1. 9. The compound of claim 1, wherein m is
 1. 10. Thecompound of claim 1, wherein p is
 0. 11. The compound of claim 1 whichis 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid dimethyl ester,2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid,2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-β-carbolin-9-yl]-ethoxy}-benzyl)-malonicacid ester dimethyl, or a salt thereof with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.
 12. Acomposition comprising the compound of claim 1, or salt thereof, and acarrier or diluent.
 13. The composition of claim 12 in unit dosage form,wherein the compound comprises from about 0.05 to about 100 mg.
 14. Thecomposition of claim 12 unit dosage form, wherein the compound comprisesfrom about 0.1 to about 50 mg.
 15. The composition of claim 12, fororal, nasal, transdermal, pulmonary, or parenteral administration.
 16. Amethod for the treatment of conditions mediated by PeroxisomeProliferator-Activated Receptors (PPAR), the method comprisingadministering to a subject in need thereof an effective amount of thecompound according to claim
 1. 17. A method for the treatment ofdiabetes and/or obesity, the method comprising administering to asubject in need thereof an effective amount of the compound of claim 1.18. The method of claim 17, wherein the effective amount of the compoundis in the range of from about 0.05 to about 100 mg per day.
 19. Themethod of claim 17, wherein the effective amount of the compound is inthe range of from about 0.1 to about 50 mg per day.